Methylphenidate sensitization is prevented by prefrontal cortex lesion.

Methylphenidate (MPD), also known as Ritalin, is a widely used treatment for Attention Deficit Hyperactivity Disorder. Repeated administration of MPD causes dose-dependent sensitization. MPD binds to dopamine (DA) transporters, and DA, therefore, remain in the synaptic cleft for longer time, resulting in an indirect DA agonist effect. MPD affects neurotransmission in brain regions including the prefrontal cortex (PFC). The mechanisms of sensitization to MPD are not clear. The aim of this study was to investigate the role of prefrontal cortex in effects of acute and chronic MPD administration, using the open field assay and male Sprague-Dawley rats with bilateral electrolytic lesions of PFC. After 1 day of control recording, following saline injection, the animals were divided randomly into three groups, (1) an intact control group, (2) a sham group, and (3) a lesion group. Then, groups 2 and 3 underwent surgery, followed by 5 days of recovery. Recordings were resumed following 1 day of saline injection and following six consecutive daily injections of 2.5mg/kg MPD, 3 days of washout period, and another day of re-challenge injection of 2.5mg/kg MPD. Acute MPD elicited increases in locomotor activity, similar to those observed from intact animals, in both sham and lesion groups. The sham group was behaviorally sensitized while the PFC lesion group failed to exhibit behavioral sensitization. These results suggest that the PFC does not interfere with the acute effects of MPD on locomotor activity but is required for development of behavioral sensitization to MPD.